The emergence of multidrug-resistant bacteria and fungi as human pathogens warrants a continued focus on the development of new pharmacophores for the treatment of these devastating and often fatal infections. The rise of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), adversely affects the efficacy of many known, standard-of-care, antibacterial agents. Evidence of the impact of these multidrug-resistant strains appears in a 2011 report from the Centers for Disease Control and Prevention (CDC) that estimates that the national incidence of invasive MRSA infections was 80,461 cases and 650 deaths. This mortality rate is among the highest recorded for bacterial infections. Likewise, listerosis, which is a common foodborne illness caused by Listeria monocytogenes, represents a serious illness afflicting elderly people, newborns, and those with impaired immune systems. Estimates suggest that L. monocytogenes causes 19% of deaths associated with the consumption of contaminated foods in the United States.
The incidence of invasive fungal infections is also on the rise due to an increasing population of critically ill patients as a result of the human immunodeficiency virus (HIV), systemic diseases such as cancer, and the increasing role of organ transplantation. The National Healthcare Safety Network (NHSN) at the CDC has reported that Candida spp. ranked fifth among hospital-acquired pathogens. Candida spp. fungi have also been reported as the fourth most common causative pathogens of nosocomial, often fatal bloodstream infections. Eukaryotic C. albicans share a close evolutionary relationship as well as many cellular mechanisms with their human hosts and present therapeutic challenges for new treatments for systemic fungal infections. There is an unquestioned need for new antimicrobials that selectively inhibit these microorganisms without causing host toxicity.
Pentamidine represents an archetypical, biscationic antibiotic with a symmetrical structure containing two amidinium functional groups separated by a flexible 1,5-diphenoxypentane spacer. Developed initially as an antiprotozoal agent, it currently finds applications in both the treatment of protozoan diseases, such as Trypanosoma brucei gambiense (West African trypanosomiasis) as well as systemic fungal infections caused by Pneumocystis jirovecii, often seen in patients with HIV. Related compounds include symmetrical bisamidines, (e.g., furimidazoline), developed principally as topoisomerase inhibitors for cancer treatments. In addition to these biscationic compounds, other hydrazone- and guanidine-containing molecules possess a range of promising biological activities including antituberculosis, anti-HIV, anticonvulsant, anticancer, anti-inflammatory, antimalarial, antibacterial, and antifungal activities. Recently, bis(N-amidino)hydrazones were reported to inhibit the calcium-dependent serine endoprotease, furin, which activates immature proteins to their functional, mature form.
Accordingly, a continuing need exists for the development of specific antifungal agents for the treatment and prevention of fungal diseases and infections.